Fragment development through off-rate screening

Fragment-based drug design enables the identification of small, low affinity (Kd ~5mM-500uM) but highly ligand efficient compounds binding to the target of interest. These hits represent good starting points for the development of cell permeable inhibitors and drugs. Hence, the next major hurdle in development of the weak affinity hit is to increase affinity and size to give lead structures which can be used to probe biology or undergo further development. Off-rate screening uses Surface Plasmon Resonance (SPR) to observe the kinetics of ligand-target interactions.

Affinity (Kd) is related to the association rate (ka) and dissociate rate (kd) of the ligand-target complex and higher affinity compounds are predominantly obtained by reducing the dissociation rate of the complex. Hence screening for compounds with slower dissociation rates provides an efficient method for finding higher affinity analogues. Another advantage of screening for slow dissociation rates by SPR is that low purity mixtures can be used. Hence chemistry can be conducted in parallel (~96 at a time) on microscale (~10 uL per reaction) without the need for purification and screened directly by SPR.

This project has a number of aspects from computational chemistry and medicinal chemistry associated with the design of the library for synthesis, conducting the microscale parallel synthesis and screening the products by SPR and would provide the opportunity to work across computational chemistry, organic chemistry and biophysical screening fields.